Is Alzheimer's field blocking R&D into other causes?
SHARON
BEGLEY, The Wall Street Journal
Friday,
April 9, 2004
©2004 Associated Press
(04-09) 06:42 PDT (AP) --
Jie Shen describes the past two years
of her scientific life as "torture," but she can't
say she wasn't warned. In the mid-1990s, as a young
researcher in the lab of a Nobel-winning neuroscientist,
she grew curious about alternatives to the leading
hypothesis of Alzheimer's disease, and in virtually
any other field she would have been free, even encouraged,
to follow her scientific curiosity wherever it led.
But her mentor warned her off. Alzheimer's, he said,
is not like other fields.
She found that out the hard way during
an odyssey that has finally culminated in the publication
of an eye-opening paper. In a nutshell, a team led
by Dr. Shen, a molecular geneticist and neurobiologist
at Harvard Medical School, Boston, shut down two
mouse genes whose human forms have been linked to
inherited forms of Alzheimer's.
According to the leading theory of
the disease, these so-called presenilin genes are
involved in the production of beta-amyloid, a protein
that forms gumball-like "plaques" in the brain.
Those plaques, in turn, are widely thought to kill
brain cells, erase synapses and memory, and lead,
ultimately and often blessedly, to death.
But adult mice missing the presenilin
genes, and hence the supposedly toxic amyloid protein,
still suffered memory problems and brain-cell death,
just as in Alzheimer's. Dr. Shen and her colleagues
concluded that amyloid is something the brain likely
needs in order to think, remember and keep neurons
alive, not something that gums it up, as the "amyloid
hypothesis" holds.
When the Harvard scientists submitted
their findings to two leading journals beginning
in 2002, they hit a brick wall. One peer-reviewer
shot back with a long list of criticisms that took
them months to address. Another demanded they figure
out the molecular mechanism behind the effects in
the mice, and then when they did that, demanded
yet more detail -- the mechanism underlying the
mechanism, as it were -- something pretty much unheard
of for a paper of this kind.
"Powerful people in this field think
that amyloid causes Alzheimer's and won't consider
research that questions the amyloid hypothesis,"
says one of the Harvard scientists. Competing theories
blame other proteins (including those called APP
and tau), toxic metals, cholesterol or inflammation
for Alzheimer's.
The Harvard team thinks it would have
been nice for the world to know its results two
years ago, not Thursday when they were finally published
in the journal Neuron. "One day," says one of the
Neuron authors, "I'll write a book, 'The Dark Side
of Science.' "
Amyloid enthusiasts deny that they
have formed some kind of cabal. They believe that
amyloid offers the best shot at defeating Alzheimer's
and so view the pursuit of other avenues as a waste
of resources. But something else seems to be at
work.
"Whenever you have a field with limited
funding, and a small number of people with big egos
who have everything invested in one idea, you have
the right chemistry for one theory to become so
pervasive nothing else can fluorish," says Zaven
Khachaturian, who ran research at the National Institute
of Aging from 1977 to 1995. He calls the dominance
of the amyloid hypothesis and the strangling of
alternatives "one of the most important issues in
science today."
The result of the amyloid orthodoxy
is that for 20 years this one hypothesis has ruled
Alzheimer's, dominating the research of scientists
seeking understanding and pharmaceutical companies
seeking treatments. "The amyloid people are very
powerful, and have been dogmatic in opposing alternative
(hypotheses)," says molecular biologist Rachael
Neve of Harvard.
Despite hundreds of experiments casting
doubt on the neurotoxicity of amyloid, maverick
and innovative ideas get crushed. As my colleague
Bernard Wysocki reported in December, after Ashley
Bush of Harvard broke with the amyloid camp, journals
rejected his papers and funding agencies turned
down his grant proposals.
"It has been very difficult to get
funding for anything that's not based on the amyloid
cascade, or to publish alternatives to the amyloid
hypothesis in top-tier journals," says Thomas Wisniewski,
associate professor of neurology and pathology at
New York University School of Medicine in New York
City.
Such dogmatism is usually a bad idea
in science, and when it comes to Alzheimer's, the
effect has been nothing short of tragic. By putting
almost all its eggs in the amyloid basket, the Alzheimer's
establishment has impeded progress on the disease.
Because research chasing the demon amyloid gets
the lion's share of financial support and dominates
the high-profile journals, antiamyloid treatments
receive most of the R&D support, too. Few other
approaches to cures are in the pipeline.
"I think we've lost some time," says
Dr. Wisniewski. Neuropathologist George Perry of
Case Western Reserve University, Cleveland, draws
an analogy to the criminal-justice system. "Executing
beta-amyloid," he says, "leaves the killer loose
in the brain."
Next week, I'll explore the failings
of the amyloid hypothesis, and discuss what has
befallen scientists who challenge it.
©2004 Associated Press
